Cocaine use is associated with behaviors that increase exposure to HIV. However, it is not known whether cocaine use accelerates the progression to AIDS, increases the incidence or severity of AIDS dementia, or increases the likelihood that an individual exposed to HIV will become infected. Some of the confusion over these possible interactions between cocaine and HIV lies in the inherent difficulties of studying human populations of drug users, including problems establishing the duration of cocaine use, the amount and formulation of cocaine consumed, the route of administration, and the concurrent use of the drugs and/or alcohol. SIV infection in macaques is an excellent model for studies of the neurological events in HIV-infected people because it causes clinical and pathological changes similar to HIV and alterations in cognitive/behavioral function similar to those seen in AIDS dementia. The SIV/macaque model has several strengths: macaques can be inoculated with molecularly cloned, biologically characterized viruses, they can be euthanized at different stages of infection to study tissue changes and virus gene expression, and macaque studies do not have the confounding effects of antiviral treatment. Further, macaques can be administered drugs such as cocaine on a known schedule to determine the effects of those drugs on cognitive/behavioral function and on the pathogenesis of SIV infection. The SIV/macaque model is currently an untapped resource for studies of the cognitive/behavioral consequences of injection drug use in the context of HIV infection. Our hypothesis is that cocaine accelerates the progression to AIDS and the development of CNS lesions and dementia, and thus augments or accelerates the production of cognitive/behavioral deficits. Further, we hypothesize that cocaine increases the susceptibility to infection in macaques exposed to SIV by the mucosal route. The proposed research will employ the SIV/macaque model of HIV/AIDS to determine whether acute or chronic cocaine use alters 1) the progression to AIDS, 2) the incidence or severity of CNS lesions, 3) cognitive/behavioral function during different stages of SIV infection, and 4) the susceptibility to infection after exposure to SIV. Cocaine is proposed as the prototypic drug of abuse in these studies due to its widespread use, its known immunosuppressive effects, its association with HIV in humans, and the absence of physical dependence following its long-term use (e.g., as contrasted with opiates).